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Cytochrome P450 2D6 as a model antigen

Christen, Urs and Holdener, Martin and Hintermann, Edith. (2010) Cytochrome P450 2D6 as a model antigen. Digestive Diseases, 28 (1). pp. 80-85.

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Official URL: http://edoc.unibas.ch/dok/A6003846

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Abstract

Cytochrome P450 2D6 (CYP2D6) has been identified as the major autoantigen in type 2 autoimmune hepatitis (AIH). However, because of a lack of appropriate animal models, the etiology of AIH is still poorly understood. We generated a mouse model for AIH using the human CYP2D6 as a triggering molecule for autoimmunity. We infected wild-type FVB mice with an adenovirus expressing human CYP2D6 (Ad-2D6) to break self-tolerance to the mouse CYP2D6 homologues. Ad-2D6-infected mice showed persistent features of liver damage including hepatic fibrosis, cellular infiltrations, focal-to-confluent necrosis and generation of anti-CYP2D6 antibodies, which predominantly recognized the identical immunodominant epitope recognized by LKM-1 antibodies from AIH patients. Interestingly, Ad-2D6 infection of transgenic mice expressing the human CYP2D6 (CYP2D6 mice) resulted in delayed kinetics and reduced severity of liver damage. However, the quantity and quality of anti-CYP2D6 antibodies was only moderately reduced in CYP2D6 mice. In contrast, the frequency of CYP2D6-specific CD4 and CD8 T cells was dramatically decreased in CYP2D6 mice, indicating the presence of a strong T cell tolerance to human CYP2D6 established in CYP2D6 mice, but not in wild-type mice. CYP2D6-specific T cells reacted to human CYP2D6 peptides with intermediate homology to the mouse homologues, but not to those with high homology, indicating that molecular mimicry rather than molecular identity breaks tolerance and subsequently causes severe persistent autoimmune liver damage. The CYP2D6 model provides a platform to investigate mechanisms involved in the immunopathogenesis of autoimmune-mediated chronic hepatic injury and evaluate possible ways of therapeutic interference.
Faculties and Departments:03 Faculty of Medicine > Bereich Operative Fächer (Klinik) > Bewegungsapparat und Integument
03 Faculty of Medicine > Departement Klinische Forschung > Bereich Operative Fächer (Klinik) > Bewegungsapparat und Integument
UniBasel Contributors:Hintermann, Beat
Item Type:Article, refereed
Article Subtype:Research Article
Bibsysno:Link to catalogue
Publisher:Karger
ISSN:0257-2753
e-ISSN:1421-9875
Note:Publication type according to Uni Basel Research Database: Journal article
Language:English
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Last Modified:24 Oct 2017 12:37
Deposited On:19 Jul 2013 07:37

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